Anesthetic compounds



Patented Nov. 21 1944 g 3 a ANESTHETICCOMPOU NDS r t William F. Ringk, Hollis, Ni 1Y.,\as sign0r to Novoa 3 colChen'lical Mfg. Cm, Inc., Brooklyn, N. ,Y., a i

corporation of;New York H lie-Drawing. Application July 29,1943, Serial No. 496,589 r 5 Claims. .(Cl. 260-472) This invention relates to a nesth etic come pounds. The principal object of the present invention is to produce aseries oftflgwlanesthetio Compounds.

The invention comprises the novel products,

the specific embodiments of which are described hereinafter by way of example and in accord ance with which I nowprefer to practise the;

invention. a

I have found in accordance with my invention a series of substances havingthe formulae: 11.. j fl anaemic o '0 eat. Alkyl ts, I

Nmotmoooomr lm-gr Alkyl,

where R=H and R'=m ethyI or et hylp NHmQtHnLCOQ. the Alkyl carbon atoms. r

These compounds are useful as anesthetics, though not restricted tosuch use, and aremade from the reactionlof ethanols with nitro benzoyl halides as set forth hereinafter. 1

Compounds falling under group 1 above are claimed in my copending application Serial No.

406,182, filed AugustQ, 1941. ing under group t2 are claimedherein. Compoundsfalling under group 3 are claimed in my JanuaryZO, 1943. i r These anesthetics, especially the higher mom-,- bers of the series, that ,is containing a relatively large number of carbon atoms in the alkyl group,

copending application \Serial No. 472,963 filed Compounds fall- Where R a lower alkyl group. In leach instance, NH Alkyl contains not more than ten,

substances are preparedin accordance with my C invention through the reaction between a series of 'alkyl halides and ethanolsdescribed below. Thesegin turn arepreacted with-nitro benzoyl,

halides as describedbelow. I t j In preparing these ethanols, the reaction mixtures are refluxed from 24 to 96 hours,depending upon the molecular weightof the alkyl group entering the molecule, It isimportant to use an excess of, the alkyl halide, generally two mols ofhalide to oneof: the ethanol, in order to force the reactionto formthe desired compound. The ollowing is an outlineof the procedure used preparing some members of thisseries. j 1 1. Preparatio nwof l jeta ethyl amino beta, beta dimethyl ethanol uu GHa V unsure-uncles CH3 To 178 gramsQmols) of beta-amino beta, beta-dimethyl'ethanoland 436grams (4 mols) of ethylbromidecontained in a flask was added 900 ccqof water. *The' reaction mixture was allowed to reflux for ,24 hours, cooled and trans ierred to a separatoryfunnel. The bottom layer consisting of unreacted ethyl bromide wassep'aare particularly valuable as surface anesthetics and find special-use accordingly inoperations such as those on the eye. Compared with butyn, which is often employed foreyeioperations, these anesthetics of my invention include compounds which, even in smallerl doses than thoseadmin equal or istered in the case of butyn, give an usually greater anestheticefi'ect.

The lower members of this series of anesthetics are alsog' suitable for use in infiltration and conduction anesthesia. They have been found to be considerably rnore .potent than.

procaine for this purpose. u The intermediates used in preparing the above I as rated and saved, an excess over the amount re quired to neutralize the HBr, of sodium hydroxide was added with cooling to the fraction remaining in the separatory funnel. f A whitesolid mass Separated from the caustic. solution which was then extractedwith ether, the ether layer separated, dried over anhydrous sodium sulfate and vacuum distilled and the fractioniboiling at.

84-93 C. at 21-24 mm. pressure wassaved.

On careful fractionation, this yields @a pure secondary amino alcohol which-has a B. P. (boil-. ing point) =167-169 (C. at atmospheric pressure.

It is awhite solid havingan M. P. (melting point) at,54.5- 57.0 C. and when sublimedlgives white, hygroscopic needles with a slight ammoniacal odor. g r

2. Preparation ofyiormal propy l amino beta dimethylethcmot r To.1'78 grams ,(2mo ls) of beta amino beta beta dimethyl ethanol and 492 grams (4 mols) of, normal propyl bromide contained in a flask was i added 900 grams of iso-propanol. The reaction mixture was allowed to reflux for 24 hours and cooled. An excess of concentrated hydrochloric acid was added to-the reaction mixture andthe mixture vacuum-distilled to remove all the water and isopropanol. To the residue remaining in the flask, an excess over the amount required to neutralize the added acid, of a 30% caustic alkali solution isadded. A white solid mass was separated from the caustic solution. This white solid mass was then extracted with ether. The ether layer was separated, dried over a suitable drying agent such as anhydrous sodium sulfiate, and the ether evaporated off. The residue was vacuum-distilled under reduced pressure and the distillate was carefully fractionated and yielded a pure secondary amino alcohol boiling at.

181-186" C. and melting at 47-49 C.' It is a white solid and when sublimed gives white, hygroscopic needles with a slight ammoniacal odor. The compound has the following formula:

It will be noted in accordance with the above examples that where the beta alkyl group attached t the nitrogen atom is ethyl, as in Example 1, that water is preferably used as a solvent.

.Where the compound contains a, propyl group instead of the ethyl group as in Example 2, isopropanol or similar inert solvent is employed.

.Instead of isopropanol, I may employ normal 1propanol or methanol. For the higher members of the series, that is, where such alkyl group contains or more carbon atoms, i. e., starting with the amyl compounds, I prefer to carry out the reaction without any solvent. the preparation of the octyl compound, I use the following procedure: 1 Y

3. Preparation of beta 1(alpha-metha/Z heptyl) amino beta, beta climethyl ethanol To 54 grams (0.6 mol) of beta amino beta beta dimethyl ethanol is added 117 grams (0.65 mol) of 2-brom-octane and this mixture refluxed for six hours and then allowed to cool. An excess of a 30% caustic alkali solution is added to the reaction mixture in the flask which causes the separation of a yellow liquid. This is extracted with ether. The ether layer is separated and dried over a suitable drying agent, such as an- For instance, in i 5. Beta-normal batyl amino beta,beta-dimethyl ethanol CH3 noomc-Nnolmm.)

6. Beta (sec; batyl) amino beta; b'eta-dimethyl ethanol 1 CH5 CH3 hydrous sodium sulfate. The ether is evaporated and the residue vacuum-distilled. On careful fractionation, there is obtained a pure secondary amino alcohol boiling at 250-255? C. The specific gravity at C. is 0.8715. The refractive index at 20 C; is 1.4516. .The compound has the following formula:

In a manner similar to the above-described preparation, the other members of this series were prepared as follows:

4. Beta-isopropyl amino beta, beta-dimethyl ethanol H0.CH .C--NHC3H1(iso) B. P.=173l77 O. a (refractive index)=l.4442. M. P.=-

fir) 10. I Beta-normal hezryl amino beta, beta-dimethyl 11 Beta (ethyl batyl) amino beta, beta dimethyl ethanol CH: C2116 HOCH2.(!3.NH.GH2(H This is a liquid compound having the following constants:

B. P. at atmospheric pressure=220-226 0. D =0.8858

. 32 C- n =1.449a

12. Beta-normal heptyl amino beta, beta dimethzll ethanol CH3 HO.ClIa.(i lNHCiH1l-,(n.)

s '13. Beta-(beta-ethyl heayl) amino-beta, betadimethyl ethanol nol series. played for the preparation of this series, the

, 2,363,088 "14.1Beta normal decyl amino beta, beta-dimethyl ethanol CH3 I no CH1. I .Naomiinc j.) CHe This is a solid material having an M. P.=50- 53 C. BJP. at 760 mm.=295-300.C. i 1

The above alkyl amino ethanols are members of the beta alkyl amino beta beta dimethyl etha- Ina similar manner to that emfractionation, this fraction yields a pure sec tive index beta alkyl amino beta methyl ethanol series may be prepared, using the known beta amino beta methyl ethanolas One of the starting materials and reacting this with the corresponding alkyl halide, whichis also known. Using this method the following secondary amino alcoholswere prepared, having the following constants;

15. Beta-normal amyl amino-beta-methyl B. P.= 210-220 C. at atmospheric pressure. D ==0.8828.

H nocnt inincsmt CH3 B. P.=2062l4 C. at atmospheric pressure. D2nl7 ,=0.88l2.

Another series of ethanols may be prepared by a method similarto the above falling under, the general heading: of beta alkyl amino beta ethyl ethanols, having the general formula:

It has been found in the preparation of ethanols .of this class that a large excess of alkyl halide is not necessary to obtain satisfactory yields.

Examples of methods employed in preparing compounds of this type areas follows: 17. Preparation of beta-ethyl amino beta-ethyl ethanol r H H noomxy-Naolm JzHa To 89 grams (1 mol) of beta-amino beta-ethyl ethanoland 119 grams (1.1 mols) of ethyl bromide contained in a flask, was added 300 cc. of water. The reaction mixture was allowed tore- C. at 5 mmlpressure was saved. On careful ondaryamino alcohol which boils at l79-l81 C. atatmospheric pressure. It isa colorless oily liquid with a slight ammoniacal odor and gives a positive nitroso test for secondaryamines. The. specific gravity=0.8880 at 27 :18. Preparation of beta-(alpha-r nethyl heptyl) amino beta ethyl ethanol edema-Neonata I Q2115 CH3 i .To 197 grams. (1.1 mols) of beta-chloro octane contained in a flask was added89 grams (1 niol) of beta-amino. beta ethyl ethanol. 1 The mixture was refluxed for a, period of24 hours and. cooled to room temperature; The reaction mixture was transferred to a separatory funnel and an excess of sodium hydroxide over the amount required to neutralize the hydrochloric acid was added with cooling. An oily layer separated 1 from the caustic solution which was then extracted with ether; the ether layer was separated.

dried over anhydrous sodium sulfate and the ether evaporated off. The residue was vacuum distilled andthe fractionboiling at over 100 0.

at 10 mm. pressure was saved. On careful fractionation, this fraction yields a pure secondary amino alcohol which boils at 2-60-262 Get atmospheric pressure. It is a colorless oily liquid with a slight ammoniacal odor andgivesa posiflux for 2 1 hours, and was then cooled and transferred to a separatory funnel; The bottom layer consisting of unreacted ethylbromide was separated and saved, an excess of sodium hydroxide over the amount required to neutralize the HBr was added with cooling,lto the fraction remaining in the separatory funnel. An oily layer separated from the caustic solution which was then extracted with ether; the ether layer was separated, dried over anhydrous sodium sulfate, and the ether evaporated oil. The residue was vacuum distilled and the fraction boiling at tive nitroso test for secondary amines, The speeific gravity equals 0.8648 at 27 C. The refractive index l n 5=l .45ll

Similarly, using beta amino alpha beta dimethyl ethanol, which is known, and reacting it with an alkyl halide, corresponding beta alkyl amino alpha beta dimethyl ethanols have been if prepared as follows:

21.- Beta-normal amyl amino alp ha, batman methyl ethanol C. The refrac-w ether.

22. Beta-isoamyl amino alpha, beta-dimethyl ethanol i i no.0 O.NHCH11(iso) CH3 CH3 B. P'.# 206213 C. at atmospheric pressure. D, =0.8574.

23. Preparation of beta ethyl amino beta, betaaimethyl ethyl para nitro benzoate :To 20 grams of beta-ethyl amino beta beta dimethyl ethanol, 8 grams of sodium hydroxide and 400 cc. of water was added all at one time with vigorous stirring, 32 grams of finely pul verized para nitro benzoyl chloride. The temperature of the reaction mixture is maintained between 304W C. and stirring continued until the nitro ester solidifies. The nitro ester is filtered oii and washed with water until free from alkali.

The nitro ester formed above may be reduced by conventional methods, using for instance, tin and hydrochloric acid, but is preferably reduced as follows:

35 grams of beta ethyl amino beta, beta-dimethyl ethyl para nitro benzoate, 70 grams of iron filings, 9.5 cc. of concentrated hydrochloric acid and 660 cc. of water are placed in a beaker and stirred vigorously. The initial heat of reaction is not permitted to go above 50 C. When the temperature of the reaction mixture starts to fall, heat is applied in order to maintain the temperature between 40-50 C. for the entire course of the reduction. Reduction is generally complete at the end of three to four hours of vigorous stirring at whichtime the reaction mixture is filtered to remove the iron sludge. '75 cc. of concentrated ammonium hydroxide solution was added to the filtrate to precipitate the amino ester which was then extracted with The ether solution was evaporated and to the amino ester was added some water and the calculated quantity of concentrated hydrochloric acid to form the mono hydrochloride. After several treatments with bone charrings in water and'a final recrystallization from methanol, the hydrochloride is obtained as a white crystalline substancemelting at 24=5.0 C.-246.5 C. The amino ester in the above example is beta ethyl amino beta, beta-dimethyl ethyl para amino About 'benzoate hydrochloride, having the following formula:

24. Beta-normal propyl amino beta, beta-dimethy ethyl para-amino benzoate hydrochloride M. P.=239-240 C. from methanol. 25. Beta-isopropyl amino beta, beta-dimethyl ethyl para-amino benzoate hydrochloride CH3 COOCHz.( J-'NHCaH1(is0).HCl

NHz

M. P.=234.5-236.0 c. from H20.

26. Beta-N-butyl amino beta, beta-dimethyl ethyl para-amino benzoate hydrochloride NHz M. P.=192.0-192.5 C from methanol 27. Beta (sec. butyl) amino beta, beta-dimethyl ethyl para-amino benzoate hydrochloride NHz . 1 M. P.=202-205 c.

M. P.=225.8-228.0 C. from water.

. 2 86351083 1 29.: Beta-N-amylamin'a new, vetwdimethyrethyl para-aminobenzoate hydrochloridre 32. Beta (e thyl bufi/I) amino beta, beta-dimethyl ethylfpard ammabenzoafe hydrochloride" M. P.=197.0- -198';0 air'rom water. f 34. Beta-(aZpha-methyl hebtyl)? ammo,

beta-dimethyl ethyl para amino benzoate hydrochloride M. P.=135--137 C. from water. The formate salt of this compound, whitecrystal s from dioxane,

melts at 107108.5 C.

35p Beta cbeta e'mm new) amiho btw; Beta dimethyl ethyl para minim: Uenzqate hydro M. P.=2.05-207 Q. Reorystallized" fi om water.

beta-methyb ethyl para-aminobenzoafe 40., y zmemo ide f beta isoam y l mm b ta ter.

hem, beta-mowing; ethyl meta amim Ben Hyroehloride" ofbet'w normaly qmyl amino 41. Formate of beta ethyl'amz'no beta ethyl para aminobeneoate I ethyl H C O CH1. .NH C2H5.formate NH2 7 This is a White crystalline compound. M. R:

4-2. Hydrochloride of beta ,(alpha methyl heptyl) amino beta ethyl-ethyl para amino-benzoate NHz This ester is a white 43. Hydroiodz'de of beta-normal butyl amino crystalline solid melting at alpha, beta-dimethyl ethyl para ammo lien I 'zoate NH2 1 M. P.=214-218 C. Recrystallizedhfrom water.. The formate salt of this compound,'white crystals from dioxane, melts at 138.2-140.4 C. 44. Hydroiodide of beta-normal amyl amino alpha, beta-dimethyl ethyl para-aminoybenzoate 2 M. P.=203205' C." Recrystallized from water. 45. "Hydroz'odide" o beta-isoamyl amino alpha," beta-dimethylethyl para amino beneoate Iii H 0000;. (LNHCeHnGSOXHI CH3 Ha v M. -P. 205-209 C. Recrystallized: from water.

The formate salt of this compound, white crystals from dioxane, melts at 134-136 C. Clinical; tests on anesthetics produced in ac-* cordance with my invention herein described have been carried out and have demonstrated that various members of the series show great strength as anesthetics giving a rapid andprofound anesthesia. 1 In several instances an eye. has been anesthetized with a single standard dose of the anesthetic and remained anesthetized for a longmonoethyl ethyl amino, benzoate katoms.

Iam aware." v o. v

The appended claims are intended to define not only an amino base or bases, but also a salt er period than any other eye anesthetic of which 1 thereof, such asthe hydrochloride, sulfate, formate, or the like.

The expression alkyl amino as used in the claims is intended to designate not'only the normal amino compounds but also any isomers of the alkyl group. The expressionsfamyl amino and-alpha methylheptyl amino similarlyde- Q fine both normal compounds and isomers there of. v r Y This application is a continuation-impart of my copending application Serial No. 406,182, filed August 9, 1941; While I have described my improvements in great detail and with respect to preferred forms thereof, I do not desire to be limited ,to such details and forms since many changes and modifica'tions may be made and the invention embodied irl widely diiierent forms without departingfrom the spirt and scope thereof in its broader aspects. Hence, I desire to cover all modifications, forms and embodiments coming within the language or scope of any one or more of the appendedclaims, I 1

What I claim as new and desire to secure by Letters Patent is:

1. Beta-alkyl amino beta-methyl ethyl amino benzoate having the formula:

in which the alkyl group o1tt1njnmbr than 10 carbon atoms. l

2. Beta-amyl amino beta-methyl ethyl para amino benzoate having the formula,

- COOCHmJNHCsHu 3. Beta ethyl. amino beta -mo'noethyl ethy amino benzoate having the formula H Nnioflmooocmfo-Nnoma C2115 4. Beta alpha methyl heptyl amino betahaving the formula WILLIAM 'FIQXRINGK.

beta substituted ethyl Certificate of Correction Patent No. 2,363,083. November21, 1944.

WILLIAM F. RINGK It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows: Page 5, second column, line 6, for that portion of the formula reading HG read H 01 line 3 1, for

read 0H3 I and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 6th day of February, A. D. 1945.

[sun] LESLIE FRAZER,

Acting Commissioner of Patents 

